Position-selective functionalizations of specific C-H bonds are in high demand. Especially, the selectivity beyond the traditional C2- and C3-manifold is highly challenging. Herein, we disclose site-selective C4/C6-H double alkylations of indoles accomplished by arene-ligand-free ruthenium(II)-carboxylate catalysis. Base-assisted C2-H ruthenation enabled the C4/C6-H dialkylations with ample substrate scope. The robust C4/C6-H alkylations were demonstrated by gram-scale syntheses and late-stage diversifications. Mechanistic studies unraveled the unique features of ruthenium(II)-catalyzed C4/C6-H indole functionalizations. (C) 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1002/chem.202003622 The authors would like to clarify that besides the para-functionalized product shown in Table S4 (page S8), they were able to detect a meta-functionalized minor byproduct, of which the data was omitted. While this finding does not show any visible inconsistency or conflict to the whole context of the manuscript, they have included these data in the Supporting Information. The original file has been replaced by an updated Supporting Information file. The authors apologize for the error and for any inconvenience caused.

Heterogeneous copper catalysis enabled photoinduced C-H arylations under exceedingly mild conditions at room temperature. The versatile hybrid copper catalyst provided step-economical access to arylated heteroarenes, terpenes and alkaloid natural products with various aryl halides. The hybrid copper catalyst could be reused without significant loss of catalytic efficacy. Detailed studies in terms of TEM, HRTEM and XPS analysis of the hybrid copper catalyst, among others, supported its outstanding stability and reusability.

We disclose the unprecedented hybrid-ruthenium catalysis for distal meta-C-H activation. The hybrid-ruthenium catalyst was recyclable, as was proven by various heterogeneity tests, and fully characterized with various microscopic and spectroscopic techniques, highlighting the physical and chemical stability. Thereby, the hybrid-ruthenium catalysis proved broadly applicable for meta-C-H alkylations of among others purine-based nucleosides and natural product conjugates. Additionally, its versatility was further reflected by meta-C-H activations through visible-light irradiation, as well as para-selective C-H activations.

A secondary phosphine oxide (SPO)-nickel catalyst allowed the activation of otherwise inert C-F bonds of unactivated arenes in terms of challenging couplings with primary and secondary alkyl Grignard reagents. The C-F activation is characterized by mild reaction conditions and high levels of branched selectivity. Electron-rich and electron-deficient arenes were suitable electrophiles for this transformation. In addition, this strategy also proved suitable to heterocycles and for the activation of C-O bonds under slightly modified conditions.

Well-defined ruthenium(II) biscarboxylate complexes enabled selective ortho-deuteration with weakly-coordinating, synthetically useful carboxylic acid with outstanding levels of isotopic labeling. The robust nature of the catalytic system was reflected by a broad functional group tolerance in an operationally-simple manner, allowing the isotope labeling of challenging pharmaceuticals and bioactive heterocyclic motifs. The synthetic power of our method was highlighted by the selective tritium-labeling of repaglinide, an antidiabetic drug, providing access to defined tritium labeled therapeutics.

Carboxylate-assisted cobalt(III)-catalyzed C-H cyanations are highly efficient processes for the synthesis of (hetero) aromatic nitriles. We have now analyzed the cyanation of differently substituted 2-phenylpyridines in detail computationally by density functional theory and also experimentally. Based on our investigations, we propose a plausible reaction mechanism for this transformation that is in line with the experimental observations. Additional calculations, including NCIPLOT, dispersion interaction densities, and local energy decomposition analysis, for the model cyanation of 2-phenylpyridine furthermore highlight that London dispersion is an important factor that enables this challenging C-H transformation. Nonbonding interactions between the Cp* ligand and aromatic and C-H-rich fragments of other ligands at the cobalt center significantly contribute to a stabilization of cobalt intermediates and transition states.

Highly enantioselective nickel-catalyzed alkene endo-hydroarylations were accomplished with full selectivity by organometallic C-H activation. The asymmetric assembly of chiral six-membered scaffolds proved viable in the absence of pyrophoric organoaluminum reagents within an unprecedented nickel/JoSPOphos manifold.

Sustainable, cobalt-catalyst enabled, synthetically significant C-F/C-H functionalizations were achieved with an ample substrate scope at an ambient temperature of 25 degrees C, thereby delivering perfluoroallylated heteroarenes. Detailed experimental and computational mechanistic studies on the C-F/C-H functionalizations provided strong support for a facile C-F cleavage.

C-H arylations of oxazolines were accomplished with a well-defined palladium catalyst derived from a secondary bisdiamantyl phosphine oxide. The single-component secondary phosphine oxide (SPO)-palladium complex enabled C-H activations with aryl bromides and challenging aryl chlorides in the absence of directing groups, setting the stage for the step-economical synthesis of pybox ligands under racemization-free reaction conditions.

C-H/C-C functionalizations with methylenecyclopropanes (MCPs) were accomplished with a versatile base-metal catalyst. A robust manganese(I) complex enabled the expedient annulation of MCPs by synthetically meaningful ketimines to deliver, upon one-pot hydroarylation, densely substituted polycylic anilines in a step-economical fashion. Mechanistic studies provided strong support for a facile organometallic C-H manganation, while typical cobalt, ruthenium, rhodium, and palladium catalysts were found completely ineffective.

C-F/C-H functionalizations proved to be viable within a versatile manganese(I) catalysis manifold. Thus, a wealth of fluorinated alkenes were employed in C-F/C-H functionalizations through facile C-H activation. The robust nature of the manganese(I) catalysis regime was among others reflected by the first C-F/C-H activation with perfluoroalkenes as well as racemization-free C-H functionalizations on imines, amino acids, and peptides.

Selectivity control in hydroarylation-based C-H alkylation has been dominated by steric interactions. A conceptually distinct strategy that exploits the programmed switch in the C-H activation mechanism by means of cobalt catalysis is presented, which sets the stage for convenient C-H alkylations with unactivated alkenes. Detailed mechanistic studies provide compelling evidence for a programmable switch in the C-H activation mechanism from a linear-selective ligand-to-ligand hydrogen transfer to a branched-selective base-assisted internal electrophilic-type substitution.

A cationic ruthenium(II)-complex enabled unprecedented C–H methylations on indoles and pyrroles. The versatile catalyst proved to be widely applicable and delivered the methylated heteroarenes with excellent levels of positional selectivity and ample substrate scope. The robustness of the catalysts was reflected by the challenging racemization-free C–H methylation of (S)-tryptophan.